# Activation Mechanism of Soluble Guanylate Cyclase

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $320,219

## Abstract

Nitric oxide (NO) signaling is essential to several physiological functions, and dysfunction in the
in this signaling cascade is implicated in multiple diseases such as erectile dysfunction, heart
disease, neurodegeneration, stroke, hypertension, and gastrointestinal disease. Soluble
guanylate cyclase (sGC) is the primary receptor for NO. NO regulates sGC at two levels and
this is consistent with pharmacological observations of NO signaling that are consistent with a
two-step activation mechanism by NO. The amplitude and duration of these effects of NO in
neuronal signaling, cardiac function, vascular tone and vasodilation are vital to proper function,
but the mechanism for the two-step activation by NO has not been thoroughly investigated. A
new paradigm for NO signaling through sGC has emerged. Understanding how sGC switches
from a low to high activation state is central to this new paradigm. In addition, sGC has become
a therapeutic target for the treatment of two forms of pulmonary hypertension: chronic
thromboembolic pulmonary hypertension and pulmonary arterial hypertension with the FDA
approved Adempas®. Our specific aims include: (i) How does NO activate sGC?, (ii) What is
the structural architecture of full-length sGC and what are the inter-domain interactions that
contribute to the activation mechanism of sGC?, and (iii) What is the mechanism of action of
Adempas® (riociguat) and related stimulators of sGC. Experimental approaches will include the
following biochemical methods: enzyme kinetics, cloning, expression, purification and
characterization of wild type and site-directed mutants of sGC, electron microscopy structural
methods, hydrogen-deuterium exchange and peptide mapping. It is a central goal of this
proposal to develop a complete molecular level view of the complex relationship between NO,
drugs like Adempas® and sGC. The extension of this work into physiological function will
provide a rational basis for the understanding and treatment of NO signaling disorders in human
disease.

## Key facts

- **NIH application ID:** 9882280
- **Project number:** 5R01GM127854-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** MICHAEL A. MARLETTA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $320,219
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882280

## Citation

> US National Institutes of Health, RePORTER application 9882280, Activation Mechanism of Soluble Guanylate Cyclase (5R01GM127854-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9882280. Licensed CC0.

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